| Budget Amount *help |
¥3,200,000 (Direct Cost: ¥3,200,000)
Fiscal Year 2000: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1999: ¥2,400,000 (Direct Cost: ¥2,400,000)
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| Research Abstract |
The combination treatment of a proton pump inhibitor (PPI) and antibiotics has been conducted as the anti-Helicobacter pylori (H.pylori) therapy, finally to rescue from gastric and duodenal ulcer diseases. PPIs including omeprazole, lansoprazole and rabeprazole are metabolized mainly by two kinds of cytochromes P450, CYP3A4 and/or CYP2C19. CYP2C19 shows the polymorphisms, which is suspected of causing the intersubject difference in the anti-H.pylori therapy. In order to figure out the role of the CYP2C19 genotype in this therapy, the plasma concentration and intragastric pH profiles after PPIs administration, the eradication ratio (anti-H.pylori efficacy), and in vitro metabolism were subjected to investigation.
CYP2C19 genotypes ofl healthy volunteers and patients were determined by PCR-RFLP method. Plasma concentration of each PPI and intragastric pH were monitored after the PPI single administration for healthy volunteers who had neither history of peptic ulcer disease, nor serum positive-H.pylori antibody. Patients with cultured H.pylori positive gastritis or peptic ulcer were treated with one of PPIs plus amoxicillin and clarithromycin for one week, and the anti-H.pylori efficacy was judged from culture, histology, and ^<13>C-urea breath test. In vitro metabolism profile was also elucidated using human liver microsomes.
The plasma concentration and intragastric pH profiles were found to be related to the CYP2C19 genotype for omeprazole or lansoprazole, not for rebeprazole. The intersubject difference in the anti-H.pylori therapy using omeprazole was also explained by the CYP2C19 genotype, whereas the anti-H.pylori efficacy in both genotype groups was almost equal for other PPIs. In vitro experiments have clarified that the relative contribution of CYP2C19 to CYP3A4 for each PPI metabolism can explain the relationships between the CYP2C19 genotype and plasma concentration, intragastric pH profiles and final anti-H.pylori efficacy with PPIs.
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